OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double‐Blind, Randomized, Placebo‐Controlled Phases of the PREEMPT Clinical Program

Abstract

(Headache 2010;50:921‐936) Objective.— To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Background.— Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Methods.— The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24‐week randomized, double‐blind phase followed by a 32‐week open‐label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155‐195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double‐blind phase, open‐label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between‐group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (≥60) Headache Impact Test‐6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double‐blind phases are presented. Results.— A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between‐group differences favoring onabotulinumtoxinA over placebo at week 24 (−8.4 vs −6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment‐related adverse events were identified. Conclusions.— The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom mea...

Disability and quality of life in headache: where we are now and where we are heading

“…There were one trial on onabotulium toxin A [5], three trials on prophylactic medications, one on levetiracetam [6] and two on b-blockers [7,8]. Four studies described a surgical approach: two were procedures for deactivation of trigger sites [9,10], one approach was the occipital nerve stimulation [11], and one approach was bariatric surgery for obese patients patients comorbid migraine [12].…”

Diagnosis, pathophysiology and management of chronic migraine: a proposal of the Belgian Headache Society

“…The two largest multicentre RCTs were those of the PREEMPT programme sponsored by Allergan [69] [70,71]. PREEMPT 1 and 2 comprised 1,384 CM patients randomized either to BoNT-A (n = 688) or to saline injections (n = 696) and followed up for 24 weeks during which they received two injection cycles.…”

“…PREEMPT 1 showed no significant difference for the primary endpoint (mean reduction of headache episodes), but secondary endpoints like reduction of headache days were in favour of BoNT-A. Mean reduction of headache days was therefore chosen as primary endpoint for PREEMPT 2 and for the pooled results [69]. BoNT-A was significantly superior over saline in mean reduction of headache days at each time points (from week 4 to week 24 primary endpoint: -8.4 BoNT-A versus -6.6 placebo; p \ 0.001; 95 % CI), in mean reduction of migraine days (p \ 0.001), 0.001).…”

Involvement of μ-opioid receptors in antinociceptive action of botulinum toxin type A

“…Moreover, BTX-A was recently registered for treatment of chronic migraine (Dodick et al, 2010) and several controlled clinical studies in other painful conditions are in progress (Jabbari and Machado, 2011;Singh, 2010). Importance of BTX-A application in clinical practice results from its unique ability to reduce pain in a long lasting manner (up to 6 months in humans).…”